The goal of this project is to develop improved pharmacotherapies for central nervous system disease based on the relation between transmitter mechanisms and clinical function. Investigations focus on the dopamine system and closely interacting pathways in relation to extrapyramidal and dementing disorders: 1. Posirion emission tomography (PET) - fluorodeoxyglucose (FDG) studies of Alzheimer's disease confirmed a predominant involvement of the parietal association cortex. Cortical dysfunction substantially precedes dementia onset; once cognitive impairment becomes evident, a marked intellectual decline attends relatively small decrements in cortical function. 2. PET directed studies of cortical transmitters revealed no neuropeptide Y abnormality in Alzheimer's disease; spinal fluid somatostatin levels are consistently reduced, to a degree which correlates with the severity of parietal lobe signs and with the magnitude of the parietal metabolic deficit. 3. The cortical representation of language function, as suggested by correlations between FDG metabolism and Boston Aphasia Examination scores, largely involves the left cerebral hemisphere, but with characteristic differences in the localization of naming, reading and writing. Apraxia to spoken command primarily localized to the left inferior frontal and superior temporal regions, while apraxia to visual imitation related mainly to the right posterior parietal lobe. 4. Parkinsonian patients, disabled by on-off responses to dopaminomimetic therapy, stabilized indefinitely on intravenously infused L-dopa, and often maintained stability on an orally administered sustained-release dopa preparation. 5. Cholecystokinin octapeptide (CCK-8) and related peptides injected systemically produced centrally mediated pharmacologic effects, apparently related to an interaction with the dopamine system. Neither parkinsonian nor psychotic symptoms, however, improved with caerulein therapy. As part of the search for alternative approaches to modifying central CCK-8 transmission, an enzyme mediating this peptide's initial proteolytic step has been identified and partially characterized.